The present invention relates to a fused tricyclic compound having aldose reductase inhibitory activity. More particularly, the invention relates to a β-carboline derivatives and a 1,3,4,9-tetrahydropyrano[3,4-b]indole derivatives having aldose reductase inhibitory activity, an aldose reductase inhibitor comprising these compounds, and a therapeutic agent comprising these compounds as the main component.
The complications of diabetes include neurosis, retinopathy, nephropathy, and the like. 10% of diabetics are afflicted by various types of complication in about ten years. 30 to 50% of diabetic patients are said to have these types of complication in 30 years.
There is a polyol pathway metabolic increase as a factor of promoting the complications of diabetes.
The polyol pathway is catalyzed by an aldose reductase and a sorbitol dehydrogenase.
The amount converted from glucose into sorbitol is very small at a normal blood glucose concentration. However, aldose reductase is activated in hyperglycemia and increases the amount of glucose flowing into the polyol pathway, resulting in an increase in the amount of production of sorbitol and fructose.
Inflow of glucose into cells easily takes place in insulin-independent organizations. Sorbitol and fructose produced in the cells are excreted only with difficulty and accumulated in the cells due to their low permeability through cell membranes.
Although nerve tissue cells, capillary wall cells, and mesangial cells are mainly involved in neurosis, retinopathy, and nephropathy, respectively, these diseases are thought to be induced by accumulation of sorbitol and a metabolic disorder of myoinositol.
Myoinositol is a component of phosphoinositide and presents in these cells at a high concentration.
Myoinositol and glucose compete each other when incorporated into cells. As a result, hyperglycemia is believed to be a cause of myoinositol reduction.
Myoinositol reduction reduces Na/K ATPase activity and causes the complications of diabetes.
Moreover, progress of research is proving that polyol metabolism is activated not only by a hyperglycemia state but also by an ischemia-reperfusion state and increased oxidative stress. Thus, the applicability of an aldose reductase inhibitor to various diseases such as arteriosclerosis, ischemia-reperfusion hindrance of the heart and brain, inflammation, sepsis, and cancer is now increasing as a main focus of attension (Diabetes Complications, Vol. 21 (1), 25-32 (2007)).
As a therapeutic agent having an aldose reductase inhibitory effect, therapeutic agents containing a compound having a carboxymethyl group structure in the molecule such as epalrestat, zenarestat, and alrestatin, therapeutic agents containing a hydantoin derivative such as sorbinil, idarestat, and ranirestat, and the like have been known.
On the other hand, a compound having a tetrahydro β-carboline derivative, particularly 2,3,4,9-tetrahydro-β-carbolin-1-one, as a mother nucleus, has been known as an antagonist of cyclin dependent kinases (WO2006/011750).